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Completed

NCT Number: NCT03463044

Safety, Tolerability and Pharmacokinetic Profiles of MOTREM (LR12) in Healthy Male Subjects

This was a single center, randomized, placebo-controlled study with a sequential i.v. dose escalation cohorts design, to assess safety, tolerability and pharmacokinetics of MOTREM (nangibotide) in healthy volunteers

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Key information

Conditions

Healthy Subjects

Age range

18 year–45 year

Sex eligibility

Male

Study type

Interventional

Phase

Phase 1

Primary location

Richmond Pharmacology Ltd.

Croydon, United Kingdom

About this study

This was a dose escalation study in healthy volunteers to evaluate the safety and pharmacokinetics of nangibotide in humans

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • healthy male
  • ≥18 to ≤45 years old
  • Body mass index (BMI) between 18-30 kg/m² inclusive
  • Written informed consent to participate.

Main Exclusion Criteria:

  • Any clinically relevant acute or chronic diseases
  • Any history of drug or alcohol abuse
  • Any History of clinical significant disease as determined by medical history, physical examination or other evaluations.

Treatment and study plan

nangibotide

Drug

Continous i.v. infusion

Other names: LR12, MOTREM

Placebo

Drug

Placebo

Other names: matched placebo

Primary outcomes

  1. Safety and Tolerability: the Number of Subjects Experiencing Treatment Emergent Adverse Events

    Time frame: 30-44 days

    The number of subjects experiencing treatment emergent adverse events was collected to assess the safety and tolerability of MOTREM (LR12) in comparison with placebo.

Secondary outcomes

  1. Pharmacokinetics (Maximum Plasma Concentration)

    Time frame: Maximum Plasma Concentration (Cmax) was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. Cmax is determined over a period of time starting from predose to 10h after start of the loading dose.

    Plasma concentrations of LR12 were measured by a validated liquid chromatography-mass spectrometry (LC-MS/MS) assay and analyzed using noncompartmental methods to obtain estimates of the pharmacokinetic parameter of Maximum Plasma Concentration (Cmax).

  2. Statistical Analysis of LR12 PK Parameters: Steady State Concentration During the Maintenance Infusion (Cavg30-465)

    Time frame: Cavg30-465 was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. Cavg30-465 is determined over a period of time starting from predose to 10h after start of the loading dose.

    Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analyzed using noncompartmental methods to obtain estimates of the PK parameter of steady state concentration during the maintenance infusion (Cavg30-465).

  3. Statistical Analysis of LR12 PK Parameters: t1/2

    Time frame: t1/2 was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. t1/2 is determined over a period of time starting from 7 h and 45 min to 10h after start of the loading dose (decaying period).

    Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analyzed using noncompartmental methods to obtain estimates of the PK parameter of terminal half-life (t1/2).

    Of note, apparent increase in half-life at increasing doses is explained by the detection of a slow elimination phase, which was below limit of quantification for the lower doses.

  4. Statistical Analysis of LR12 PK Parameters: AUC0-t

    Time frame: AUC0-t was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. AUC0-t is determined over a period of time starting time zero (predose) to the time of last observed concentration (t).

    Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analyzed using noncompartmental methods to obtain estimates of the PK parameter of the area under the plasma concentration curve (h.ng/mL) from time zero (predose) to the time of last observed concentration (t) measured (which can go up to 10h post loading dose start) using a linear trapezoidal method (AUC0-t).

  5. Statistical Analysis of LR12 PK Parameters: AUC0-∞

    Time frame: AUC0-∞ was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. AUC0-∞ is determined over a period of time starting time zero (predose) to infinity (cf. extrapolation formula in the above section).

    Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analyzed using noncompartmental methods to obtain estimates of the PK parameter of AUC0-∞.

    AUC0-∞ represents the area under the plasma concentration-time curve (h.ng/mL) from time 0 to infinity (AUC0- ∞= AUC0-t + [Ct/ke], where Ct = the observed concentration of drug for the last sample on the PK profile in which drug was detected, and ke represents the terminal rate constant). The percentage of extrapolation of AUC0-∞ should not exceed 20%.

  6. Statistical Analysis of LR12 PK Parameters: CL

    Time frame: CL was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min (465 min). CL is calculated based on the perfusion rate (ng/kg/h) and the concentration at the end of perfusion (7h45min = 465min).

    Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analyzed using noncompartmental methods to obtain estimates of the PK parameter of systemic clearance (CL). The systemic clearance was estimated using the formula: CL = K0/ Css where K0 is the perfusion rate (ng/kg/h) and Css is the concentration at the end of perfusion (C at 465 min).

    Of note, this narrow range of the clearance values indicates that the apparent increases in t1/2 and volume of distribution as a function of doses are not due to a non-linearity in the pharmacokinetics, but to the limit of quantification of the bioanalytical assay.

  7. Statistical Analysis of LR12 PK Parameters: Volume of Distribution (V)

    Time frame: V was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. V is derived from both CL and ke which are calculated from the LR12 concentration time curve from predose to 10h after loading dose start.

    The volume of distribution was estimated according to the following equation: V= CL x MRT (mean residence time). However, regarding administration procedures, MRT could not be calculated precisely. Furthermore, in some cases MRT could not be estimated. Thus, the following formula was used V = CL / ke.

    The terminal rate constant (ke) was estimated by log-linear regression analysis on data points visually assessed to be on the terminal log-linear phase.

    Of note, it can be said that this apparent increase in V is also explained by the detection of a slow elimination phase, which was below limit of quantification for the lower doses.

  8. Statistical Analysis of LR12 PK Parameters: Tmax

    Time frame: tmax was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. tmax is determined over a period of time starting from predose to 10h after start of the loading dose.

    Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analysed using noncompartmental methods to obtain estimates of the PK parameter of the time at which Cmax is apparent, identified by inspection of the plasma drug concentration vs.time data by WinNonlin (tmax).

  9. Statistical Analysis of LR12 PK Parameters: t Last

    Time frame: t last was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. t last is determined as the time of last observed concentration which can go up to 10h after loading dose start.

    This PK parameter was calculated from measured plasma concentrations of LR12 and it represents the time of last observed concentration.

Sponsors and collaborators

Lead sponsor

Inotrem

Industry

Collaborators

  • Richmond Pharmacology Limited

Registry information

Official study title

A Phase I, Randomised, Placebo Controlled Study to Assess the Safety, Tolerability and Pharmacokinetic Profiles of Ascending, Single, Intravenous Doses of MOTREM (LR12) in Healthy Male Subjects

Important dates

Study start
2016
Primary completion
2016
Study completion
2016
First posted
Mar 13, 2018
Registry last updated
Feb 10, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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